AB0511 A PHASE 1, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE- AND MULTIPLE-DOSE ESCALATION STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF PF-06835375 IN PATIENTS WITH SEROPOSITIVE SYSTEMIC LUPUS ERYTHEMATOSUS OR RHEUMATOID ARTHRITIS
Authors: S. Cohen, J. Beebe, V. Chindalore, S. Guan, M. Hassan-Zahraee, C. Hyde, S. Koride, R. Levin, S. Lubaczewski, M. Salganik, A. Sloan, E. Stevens, E. Peeva, M. Vincent, D. Martin, M. Chu
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> PF-06835375 is a humanised, afucosyl IgG1 antibody selective against C-X-C chemokine receptor type 5 (CXCR5), a receptor expressed on B cells, bona fide T follicular helper (Tfh) cells and circulating T follicular helper-like (cTfh) cells. PF-06835375 is in development for autoimmune diseases through depletion of CXCR5-positive B and Tfh cells and antagonism of C-X-C motif chemokine ligand 13-dependent signalling. <h3>Objectives</h3> This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of PF‑06835375 in patients with seropositive systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). <h3>Methods</h3> This multi-centre, double-blind, placebo-controlled Phase 1 study enrolled patients aged 18–70 years with seropositive SLE (diagnosed by Systemic Lupus International Collaborating Clinics classification criteria, and positive anti-nuclear antibody titres ≥1:80 and/or anti-dsDNA and/or anti-Smith antibodies) or RA (diagnosed by 2010 ACR/EULAR criteria and positive rheumatoid factor and/or anti-citrullinated peptide antibody), with no minimum disease activity requirement. Patients were randomised to intravenous (IV) PF-06835375 (0.03, 0.1, 0.3, 1, 3 or 6 mg) or placebo in 6 sequential single ascending dose (SAD) cohorts, or to subcutaneous (SC) PF‑06835375 (0.3, 1, 3, 6 or 10 mg) or placebo administered on Days 1 and 29 in 5 multiple ascending dose (MAD) cohorts. Pre-and post-dose corticosteroids were permitted to manage infusion or injection reactions at the investigator's discretion. Primary endpoints were incidence of treatment-emergent adverse events (TEAEs) of all casualties, infections and laboratory, vital sign and electrocardiogram (ECG) abnormalities. Secondary endpoints were PK parameters, change in circulating CXCR5-positive B- and cTfh-cell counts and incidence of anti-drug antibodies (ADAs). <h3>Results</h3> In total, 74 patients were randomised and 73 were treated (SAD cohorts: SLE, n=17; RA, n=14; MAD cohorts: SLE, n=22; RA, n=20). Corticosteroids were given in PF-06835375 3 and 6 mg IV cohorts and 3, 6 and 10 mg SC cohorts. Mean (standard deviation) age was 53.3 (10.7) years. Most patients were female (n=65, 89.0%) and White (n=54, 74.0%). In total, 62 patients (84.9%) experienced TEAEs; most were mild or moderate. Serious adverse events were reported in 3 patients (9.7%). One patient (1.4%) discontinued due to a TEAE of disease progression (placebo SC cohort). The most common TEAEs were headache (n=18, 24.7%), pyrexia (n=11, 15.1%) and urinary tract infection (n=9, 12.3%). All infections were mild or moderate. Laboratory abnormalities (placebo IV SAD, PF-06835375 1 mg IV SAD and PF‑06835375 3 mg SC MAD) and ECG abnormalities (PF-06835375 0.1, 1 and 6 mg IV SAD) were reported as TEAEs in individual patients. No deaths occurred. In IV SAD cohorts, median T<sub>max</sub> ranged from 2–4 h and mean CL ranged from 0.021–0.313 L/h. Exposure (AUC<sub>inf</sub> and C<sub>max</sub>) generally increased dose-proportionally for doses ≤1 mg and more than dose‑proportionally for doses &gt;1 mg. In SC MAD cohorts, median T<sub>max</sub> ranged from 121–171 h and mean CL/F ranged from 0.07847–0.1171 L/h. Exposure (AUC<sub>tau</sub> and C<sub>max</sub>) generally increased dose-proportionally. B- and cTfh-cell counts generally showed dose-dependent reductions across cohorts (range of mean maximum depletion: 67.3–99.3% and 62.4–98.7%, respectively, in SAD, and 91.1–99.6% and 89.5–98.1%, respectively, in MAD cohorts; Figure 1). Mean duration of B- and cTfh-cell depletion extended up to 71.6 and 62.0 days, respectively, in SAD, and 78.5 and 109.5 days, respectively, in MAD cohorts. ADA data did not suggest any clinically relevant impact on PK, PD or safety. <h3>Conclusion</h3> PF-06835375 was generally well tolerated in patients with seropositive SLE and RA with potent and prolonged B- and cTfh-cell depletion, supporting further development as a treatment for autoimmune diseases. <h3>Acknowledgements</h3> This study was sponsored by Pfizer Inc. Medical writing support, under the direction of the authors, was provided by Sonya Frazier, PhD, CMC Connect, a division of IPG Health Medical Communications, and was funded by Pfizer Inc, New York, NY, USA, in accordance with Good Publication Practice (GPP 2022) guidelines (Ann Intern Med 2022; 175: 1298-1304). <h3>Disclosure of Interests</h3> Stanley Cohen Consultant of: Pfizer Inc, Jean Beebe Employee of: Former employee of Pfizer Inc, Vishala Chindalore: None declared, Shunjie Guan Employee of: Employee of Pfizer Inc, Mina Hassan-Zahraee Employee of: Employee of Pfizer Inc, Craig Hyde Employee of: Employee of Pfizer Inc, Sarita Koride Employee of: Employee of Pfizer Inc, Robert Levin Speakers bureau: AbbVie and GlaxoSmithKline, Consultant of: AbbVie, AstraZeneca and Janssen, Shannon Lubaczewski Employee of: Employee of Pfizer Inc, Mikhail Salganik Employee of: Employee of Pfizer Inc, Abigail Sloan Employee of: Employee of Pfizer Inc, Erin Stevens Employee of: Employee of Pfizer Inc, Elena Peeva Employee of: Employee of Pfizer Inc, Michael Vincent Shareholder of: Pfizer Inc, Employee of: Employee of Pfizer Inc, David Martin Employee of: Employee of Pfizer Inc, Myron Chu Employee of: Employee of Pfizer Inc.